The formation of pharmaceutical spheroids using extrusion and spheronisation techniques is well known in the pharmaceutical industry and typically requires the inclusion of a spheronising aid to provide formulations with the necessary structural integrity, plasticity and water-absorbing capacity required for successful formation of spheroids.
Pharmaceutical spheroids are typically manufactured on an industrial scale by firstly mixing the active ingredient(s), spheronising aid and any other excipients in a suitably sized mixer or granulator, e.g. a Vactron 300 or a Collette Gral 300, extruding the mixture/granulate in an extruder such as a Nica E140 extruder, before spheronising the extrudate using a spheroniser, e.g. Caleva or Nica S450 spheroniser, and finally drying the resulting spheroids in a suitable dryer such as a fluid bed dryer of the type manufactured by Glatt and Aeromatic Fielder.
The spheronising aid used routinely in the pharmaceutical industry is microcrystalline cellulose.
A problem which has been observed with the use of microcrystalline cellulose is the degradation of certain drugs during prolonged storage.
For instance, we have found that in microcrystalline cellulose-containing spheroids, hydromorphone hydrochloride undergoes some degradation when stored at 25° C./60% RH. We have found that this degradation of the product is due to an incompatibility between hydromorphone hydrochloride and microcrystalline cellulose catalysed by the presence of moisture. Spheroids made mainly of microcrystalline cellulose usually retain approximately 5% moisture.
Basit et al. (1999) have reported the occurrence of instability of the highly water-soluble drug, ranitidine, when formulated as a pellet dosage form containing in excess of 60% microcrystalline cellulose, the instability involving chemical degradation of the drug by means of a complex three-way interaction between ranitidine, microcrystalline cellulose and water. The authors describe the preparation of pharmaceutical spheroids of ranitidine hydrochloride, which utilise glyceryl monostearate and barium sulphate in place of microcrystalline cellulose, using small scale laboratory equipment.
Newton et al. (2004) describe the laboratory scale preparation of pharmaceutical spheroids containing either barium sulphate or diclofenac sodium as a model drug and glyceryl monostearate as a total replacement for microcrystalline cellulose.
Chatchawalsaisin et al. (2005) describe the laboratory scale preparation of spheroids containing diclofenac sodium as a model drug and glyceryl monostearate as a total replacement for microcrystalline cellulose.
A problem with the work described by Basit et al., Newton et al. and Chatchawalsaisin et al. is that operating the processes described using industrial scale equipment results in fragmented spheroids which cannot be used commercially.
WO 00/09639 (Fuisz Technologies Limited) describes the preparation of microspheres containing fatty ester combinations and optional surfactants or emulsifiers as processing aids and active agent(s) under liquiflash conditions using the spinning devices and processes as described in U.S. Pat. Nos. 5,458,823; 5,638,720; and 5,851,454.
There exists a need in the art for alternative pharmaceutical compositions in the form of spheroids comprising a chemically-compatible spheronising aid and an active ingredient, which are free or substantially free of microcrystalline cellulose and which preferably can successfully be manufactured on an industrial scale for commercialisation. In particular, the active ingredient may be one which is sensitive to chemical degradation in the presence of microcrystalline cellulose.
Milojevic et al. (1996) describe the preparation of pellets containing glucose, microcrystalline cellulose and glyceryl monostearate by extrusion and spheronisation, and the coating of these pellets with an amylose-Ethocel® formulation using a laboratory-scale fluid bed coater.
Chopra et al. (2002) describe pellets containing paracetamol, microcrystalline cellulose, glyceryl monostearate and barium sulphate, which were produced using laboratory scale extrusion and spheronisation apparatus, before being coated with a 3% solution of ethylcellulose in ethanol containing 17.5% of povidone.
Bashaiwoldu et al. (2004) describe the production of spherical pellets containing paracetamol, microcrystalline cellulose and glyceryl monostearate by the processes of extrusion and spheronisation, and the coating of these pellets with an aqueous dispersion of ethyl cellulose-containing dibutylsebacate, oleic acid and ammonium hydroxide solution using a fluid bed coater.
There remains a further need in the art for a pharmaceutical composition in the form of coated spheroids comprising a chemically-compatible spheronising aid and an active ingredient, which are free or substantially free of microcrystalline cellulose and which preferably can successfully be made on an industrial scale for commercialisation. In particular, the active ingredient may be one which is sensitive to chemical degradation in the presence of microcrystalline cellulose.